Oxidative stress is caused predominantly by accumulation of hydrogen peroxide and distinguishes inflamed tissue from healthy tissue. Hydrogen peroxide could potentially be useful as a stimulus for targeted drug delivery to diseased tissue. However, current polymeric systems are not sensitive to biologically relevant concentrations of H2O2 (50-100 μM). The contribution of oxidative stress and reactive oxygen species (ROS) to the development of numerous diseases has resulted in a research focus to create ROS-specific detection systems and ROS-responsive micro-detection systems or nanocarriers. See, e.g., Li, C. H., et al, Macromolecules 2011, 44, 429; Van de Bittner, G. C., et al., J. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 21316; Sella, E., et al, J. Am. Chem. Soc. 2010, 132, 3945, Srikun, D. et al, J. Am. Chem. Soc. 2008, 130, 4596; Lee, D., et al, Nat. Mater. 2007, 6, 765; Chang, M. C. Y., et al, J. Am. Chem. Soc. 2004, 126, 15392; Yu, S. S., et al, Biomacromolecules 2011, 12, 4357; Broaders, K. E., et al, J. Am. Chem. Soc. 2011, 133, 756; Wilson, D. S., et al, Nat. Mater. 2010, 9, 923; Rehor, A., et al, Langmuir 2005, 21, 411; Napoli, A., et al, Nat. Mater. 2004, 3, 183; Khutoryanskiy, V., et al, Pure Appl. Chem. 2008, 80, 1703; Allen, B. L., et al, ACS Nano 2011, 5, 5263.
Oxidative stress is a condition in which the balance of oxidative and reducing species within cellular environments has been disturbed. Once out of balance, ROS such as superoxide, hydrogen peroxide, and hydroxide radicals can damage cellular components. Geronikaki, A. A., et al, Comb. Chem. High Throughput Screening 2006, 9, 425.
Although some ROS are key to cell signaling and defense mechanisms, these chemicals also contribute to various diseases. See, e.g., Finkel, T. Curr. Opin. Cell Biol. 2003, 15, 247; Cachofeiro, V., et al., J. Kidney Int. 2008, S4; Drechsel, D. A., et al, Free Radic. Biol. Med. 2008, 44, 1873; Liou, G. Y., et al, Free Radical Res. 2010, 44, 479.
Methods of selective delivery of therapeutic and diagnostic reagents to sites undergoing oxidative stress would prove useful for the numerous diseases characterized by high concentrations of ROS. Polymer-based nano- and microparticles are especially useful because they can be tailored to degrade upon encountering certain stimuli, such as enzymatic removal of a protecting group, pH, light, and H2O2. See, e.g., Esser-Kahn, A. P., et al, Macromolecules 2011, 44, 5539; Seo, W., et al, J. Am. Chem. Soc. 2010, 132, 9234; Dewit, M. A., et al., J. Am. Chem. Soc. 2009, 131, 18327; Murthy, N., et al, J. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 4995; Murthy, N., et al, J. Am. Chem. Soc. 2002, 124, 12398; Sankaranarayanan, J., et al, ACS Nano 2010, 4, 5930; Goodwin, A. P., et al, J. Am. Chem. Soc. 2005, 127, 9952; Fomina, N., et al, J. Am. Chem. Soc. 2010, 132, 9540; Sella, E., et al, J. Am. Chem. Soc. 2010, 132, 3945; Lee, D., et al, Nat. Mater 2007, 6, 765; Rehor, A., et al, Langmuir 2005, 21, 411; Avital-Shmilovici, et al, Bioorg. Med. Chem. 2010, 18, 3643; Heffernan, M. J., et al, Bioconjugate Chem. 2005, 16, 1340.
Upon encapsulation, nanoparticles can provide improved pharmacokinetics, as the therapeutic drug is protected from the physiological environment and selected release allows for lower drug loading through effective site delivery. See, e.g., Petros, R. A., et al, Nat. Rev. Drug Discovery 2010, 9, 615. There are few, if any, polymeric systems able to undergo degradation and cargo release on encountering biologically relevant (50-100 μM) H2O2 concentrations. One important study showed a polymeric carrier responsive to 1 mM H2O2 in a useful time frame using dextran reversibly modified with aryl boronic esters, this system utilized a carbonate ester linkage, and took advantage of a solubility switching mechanism to release its payload. See, Broaders, K. E., et al, J. Am. Chem. Soc. 2011, 133, 756.
Notably, this study also demonstrated the advantage of such boronic ester stabilized nanomaterials for promoting immune activation by antigen-presenting cells.